Aspartylglucosaminuria via the AGA Gene

Aspartylglucosaminuria (AGU) is a severe lysosomal storage disorder that involves the central nervous system and causes skeletal abnormalities as well as connective tissue lesions. The most characteristic feature is progressive mental retardation. Affected individuals tend to have a characteristic facial appearance that includes widely spaced eyes (ocular hypertelorism), small ears, and full lips. People with this condition may also have bones that become progressively weak and prone to fracture (osteoporosis), an unusually large range of joint movement (hypermobility), and loose skin. Individuals with AGU appear normal during infancy and have a lifespan of about 25 to 45 years (Aronson 1999).

Aspartylglucosaminuria is a rare autosomal recessive disorder present mostly in the Finnish population (Aronson 1999) with an incidence of 1 in 18,500, with about 200 reported cases and a carrier frequency of 2.5-3%. The incidence in the rest of the world population is unknown. AGU is caused by mutations in the aspartylglucosaminidase (AGA) gene. AGA is responsible for the production of a lysozomal enzyme aspartylglucosaminidase, which is involved in the breakdown of complexes of sugar molecules (oligosaccharides) attached to proteins (glycoproteins). AGA mutations result in the absence or shortage of the AGA enzyme in lysosomes, preventing the normal breakdown of glycoproteins. As a result, glycoproteins buildup, disrupting normal functions of the cell and can result in destruction of the cell, particularly nerve cells in the brain. Loss of these cells causes many of the signs and symptoms of aspartylglucosaminuria.

A specific mutation (Cys163Ser) has been identified in over 98% of the affected Finnish population. So far there are about 30 other rare family AGA alleles that have been characterized at the molecular level in the world's population. Causative mutations include missense, nonsense, splicing, and small deletions and insertions.

AGA is the only gene known to be causative for aspartylglucosaminuria. A specific mutation (Cys163Ser) is concentrated in over 98% of the Finnish population. So far there are about 30 other rare family AGA alleles that have been characterized at the molecular level in the world's population.

This test provides full coverage of all coding exons of the AGA gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).